Tadpoles for MS drugs

Mannioui A, Vauzanges Q, Fini JB, Henriet E, Sekizar S, Azoyan L, Thomas JL, Pasquier DD, Giovannangeli C, Demeneix B, Lubetzki C, Zalc B. The Xenopus tadpole: An in vivo model to screen drugs favoring remyelination.Mult Scler. 2017 Jul 1:1352458517721355. doi: 10.1177/1352458517721355. [Epub ahead of print]

BACKGROUND:

In multiple sclerosis, development of screening tools for remyelination-promoting molecules is timely.

OBJECTIVE:

A Xenopus transgenic line allowing conditional ablation of myelinating oligodendrocytes has been adapted for in vivo screening of remyelination-favoring molecules.

METHODS:

In this transgenic, the green fluorescent protein reporter is fused to E. coli nitroreductase and expressed specifically in myelinating oligodendrocytes. Nitroreductase converts the innocuous pro-drug metronidazole to a cytotoxin (cell killing drug) . Spontaneous remyelination occurs after metronidazole-induced demyelinating responses. As tadpoles are transparent, these events can be monitored in vivo and quantified. At the end of metronidazole-induced demyelination, tadpoles were screened in water containing the compounds tested. After 72 h, remyelination was assayed by counting numbers of oligodendrocytes per optic nerve.

RESULTS:

Among a battery of molecules tested, siponimod, a dual agonist of sphingosine-1-phosphate receptor 1 and 5, was among the most efficient favoring remyelination. Crispr/cas9 (gene excising) gene editing showed that the pro-myelinating effect of siponimod involves the sphingosine-1-phosphate receptor 5.

CONCLUSION:

This Xenopus transgenic line constitutes a simple in vivo screening platform for myelin repair therapeutics. We validated several known pro-myelinating compounds and demonstrated that the strong remyelinating efficacy of siponimod implicates the sphingosine-1-phosphate receptor 5.

Whilst we have been hearing about monkey work and you know about the meecie stuff, but there is a movement to replace such animals with animals that are lower down the  chain of sentience. We recently heard about an EAE model in Zebra fish. They have transparent bodies and you can make their nerves or oligodendrocytes "glow in the dark" so you can watch things happening in real time.

So this study moves down the evolutionary ladder and moves us to amphibians. Xenopus is the African clawed toad, that many of you may have seen at school.   This study makes tadpoles with oligodendrocytes that glow in the dark and have been engineered so that they kill them in response to a drug. The default then is repair and remyelination.  So its abit like the chemical-induced demyelination in mice. 

In this study they test to see if drugs will make the myelin appear quicker.

In this study they report that that siponimod is one of the best agents to promote myelin. Is this good and bad news? 

The good news therefore is that here you have an agent that can block the immune response by modulating Sphingosine-1 phosphate one IS1P1) receptor and block relapsing EAE but as shown here it can promote remyelination, via an action on Sphingosine-1-phosphate five (S1P5) receptor. Siponimod has been shown to inhibit secondary progressive MS in phase II, so it could be round the corner from use. 

But the bad news is it does not appear to make miraculous recoveries, and so if this is remyelinating it warns that we have to be realistic of what remyelination therapies may offer. Furthermore remyelinating a nerve that will remyelinate any way may not be the same as trying to remyelinate chronic gliotic lesions.

Next question what is the difference between siponimod and fingolimod? Fingolimod targets S1P1 and S1P5 and also S1P3, and S1P4. there are many inferences that fingolimod was also remyelinatory, but there was contradictory evidence, but remember this agent failed in progressive MS. Was this because they didn't measure hand function?

You asked which compounds were screened

As you can see there is Biotin, Clemastine, Benztropine, fingolimod. At the top of the pile was Clemastine, albeit at a much higher doses than UC-42-WP04, then siponimod and then fingolimod, RXR and Bentropine. At the bottom of the pile was Lithium and MDL29951